Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(O)C.[CH3:14][N:15]([CH2:35][C@@H:36]1[C:39]2[CH:40]=[C:41]([O:46][CH3:47])[C:42]([O:44][CH3:45])=[CH:43][C:38]=2[CH2:37]1)[CH2:16][CH2:17][CH2:18][N:19]1[C:29](=[O:30])[CH2:28][C:27]2[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=2)[CH2:21][CH2:20]1>ClCCl>[CH3:14][N:15]([CH2:35][C@@H:36]1[C:39]2[CH:40]=[C:41]([O:46][CH3:47])[C:42]([O:44][CH3:45])=[CH:43][C:38]=2[CH2:37]1)[CH2:16][CH2:17][CH2:18][N:19]1[C:29](=[O:30])[CH2:28][C:27]2[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=2)[CH2:21][CH2:20]1.[C:1]([O-:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7]
Reactant: O=C(O)CCCCC(=O)O
Agent: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Solvent: CCO
Solvent: ClCCl
Product: O=C([O-])CCCCC(=O)[O-]

Procedure:
Ivabradine adipate can be obtained by adding adipic acid, e.g. about one equivalent, in a suitable solvent, such as ethanol, to a solution of ivabradine in a suitable solvent, such as dichloromethane. Crystalline ivabradine adipate product can be obtained by removal of the solvent, e.g. under vacuum at about 40° C. Crystalline ivabradine adipate can also be obtained by adding a solution of adipic acid in water to a solution of ivabradine in ethanol, and removal of the solvent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:22]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:22]=3[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: COC(=O)COc1cc(C)ccc1CCl
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C)ccc1COc1ccc(-n2nc(C)n(C(F)F)c2=O)c(F)c1
Yield: 79.1 %

Procedure:
By the method of Example 1, Step I, 2.0 g (0.0077 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step E) and 3.53 g (0.0151 mole) of methyl (2-chloromethyl-5-methylphenoxy)acetate were reacted in the presence of 1.60 g (0.0116 mole) of anhydrous potassium carbonate in 40 mL of N,N-dimethylformamide, yielding 2.75 g of methyl [2-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]-5-methylphenoxy]acetate. The NMR spectrum was consistent with the proposed structure. NMR: 2.30 (s, 3H); 2.44 (s, 3H); 3.78 (s, 3H); 4.70 (s, 2H); 5.18 (s, 2H); 6.60-7.36 (m, 7H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:11])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][C:32](Br)=[O:33].O>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][N:7]([C:8]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:11])[C:32](=[O:33])[CH2:31][Br:30])(=[O:3])[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CC(=O)OCCNc1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)OCCN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
A mixture of 2.5g (0.0074 M) of 2-(2-acetoxyethylamino)-5-chloro-2'-fluorobenzophenone and 5g (0.0362 M) of potassium carbonate in 25 ml of dry chloroform was treated with 2.0g (0.0096 M) of bromoacetyl bromide over a 20 minute period with stirring. The mixture was stirred for 1 hour at room temperature when 25 ml of water was added, and the chloroform layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in 10 ml of benzene, and chromatographed over 100g of Florisil. Elution with 1 l. of benzene gave 0.2g of an oil and elution with 1.5 l. of ether and 1 l. of ethyl acetate gave 1.8g and 1.0g, respectively of a colorless oil which were combined and recrystallized from a mixture of dichloromethane and petroleum ether to give the above named product as white prisms, m.p. 84°-88°.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[N:43]([CH3:47])[N:42]=[C:41]2[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:41]4[C:40]5[C:44](=[CH:45][CH:46]=[C:38]([Cl:37])[CH:39]=5)[N:43]([CH3:47])[N:42]=4)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(Cl)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(Cl)ccc21
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 79.4 %

Procedure:
In a round-bottomed flask 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (150 mg, 0.26 mmol) and 5-chloro-1-methyl-3-tributylstannanyl-1H-indazole (372 mg, 0.45 mmol) were dissolved in DMF (2.4 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and copper(I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 3.5 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2% MeOH) to isolate 137 mg (80%) of 2-(5-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10]([C:12]([CH2:17][CH3:18])(CO)CO)[CH3:11].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:10]([C:12]1([CH2:17][CH3:18])[CH2:1][O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH3:11]
Reactant: CCC(CC)(CO)CO
Reactant: COc1cscc1OC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCC1(CC)COc2cscc2OC1
Temperature: 25 °C
Yield: 68 %

Procedure:
3,4-Dimethoxythiophene (5.0 g, 34.7 mmol), 2,2-diethyl-1,3-propanediol (36.4 mmol), toluenesulfonic acid (0.2 g), and dry toluene (200 mL) were placed in a 500 mL round bottom flask equipped with a soxhlet extractor that contained a molecular sieve (4A)-filled extraction thimble. The solution was refluxed for 12 h under argon atmosphere, then cooled to 25° C. The solvent was removed under reduced pressure, the mixture diluted with 250 mL diethyl ether, extracted with 5% ammonium hydroxide (200 mL), and the extracted with water (2×200 mL). The organic layer was dried over anhydrous magnesium sulphate and the ether distilled off under reduced pressure, leaving an oil. This oil was further purified using column chromatography (silica and hexanes/ethyl acetate, 90/10) to yield 3,3-diethyl-3,4-dihydro-2H-thieno[3,4-b][1,4]dioxepine as a colourless oil in 68% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]3[N:9]=2)=[C:4]([S:22][CH2:23][CH3:24])[CH:3]=1.Cl[C:26]1C=CC=C(C(OO)=[O:33])[CH:27]=1.C(=O)([O-])O.[Na+].[S:41]([O-:45])([O-])(=[O:43])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=[C:10]3[N:9]=2)=[C:4]([S:22]([CH2:23][CH3:24])=[O:33])[CH:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=[C:10]3[N:9]=2)=[C:4]([S:41]([CH2:26][CH3:27])(=[O:45])=[O:43])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1cc(Br)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(Br)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Product: CCS(=O)c1cc(Br)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-bromo-2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.40 g) and chloroform (5 ml), 3-chloroperbenzoic acid (purity: not less than 65%, 0.29 g) was added under ice-cooling, then heated to room temperature, and stirred for 2 hours. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.26 g of 2-(4-bromo-2-ethylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, Present Compound 239) and 0.17 g of 2-(4-bromo-2-ethylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, Present Compound 240).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](Cl)=[O:10])[CH:4]=1.Cl.NC[C:15]([NH:17][CH3:18])=[O:16].[CH2:19]([N:21](CC)CC)C>C1COCC1.C(#N)C>[CH3:19][NH:21][C:15]([N:17]([CH3:18])[C:9]([C:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[CH:7][N:6]=1)=[O:10])=[O:16]
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CCN(CC)CC
Reactant: CNC(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: CNC(=O)N(C)C(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of 4-chloropyridine-2-carbonyl choride HCl (2.00 g, 9.41 mmol) in THF (16.4 mL) and acetonitrile (9.4 mL) was added 2-amino-N-methylacetamide hydrochloride (1.29 g, 10.35 mmol, 1.1 eq) and triethylamine (5.25 mL, 37.6 mmol, 4.0 eq) at 0° C. The resulting dark brown reaction mixture was stirred at RT for 2 h. The volatile solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified on MPLC (biotage) eluted with 100% EtOAc to give 1.4 g (65.3%) of 4-chloropyridine-2-carboxylic acid methylcarbamoyl-N-methylamide as a tan solid: TLC (75% EtOAc/hex), Rf=0.14; MS LC-MS [M+H]+=228.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)[CH:18]([CH3:20])[CH3:19])[CH:13]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:53]1[O:54][CH:55]=[CH:56][CH:57]=1)CCC.[Cl-].[Li+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:54]1[CH:55]=[CH:56][CH:57]=[C:53]1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]([C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)([OH:45])[CH:18]([CH3:20])[CH3:19])[CH:11]=[CH:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(O)(c1ccc2cc(-c3ccco3)ccc2c1)c1c[nH]cn1

Procedure:
6-[1-Hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthyl trifluoromethanesulfonate (2.0 g), 2-(tributylstannyl)furan (1.26 mL), tetrakis(triphenylphosphine)palladium (115 mg) and lithium chloride (259 mg) were dissolved in DMF (10 mL) and heated at 80 for 4 h. The reaction mixture was diluted with water, extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluent; hexane:THF=4:1) and crystallized from ethyl acetate-hexane to give the titled compound (1.48 g) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:18]3[CH2:19][CH2:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: c1ccc2c(c1)CCNC2
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCc4ccccc4C3)CC2)cc1

Procedure:
3.0 g of 1-(4-nitrophenyl)-4-piperidone and 1.8 g of 1,2,3,4-tetrahydroisoquinoline were reacted as in Example 1.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=[CH:4][N:3]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH2:14]([S:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1)(=[O:13])=[O:12])[CH3:15]
Reactant: NCC1CCOCC1
Reactant: CCS(=O)(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Product: CCS(=O)(=O)c1cnc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 2-chloro-5-(ethylsulfonyl)-3-nitropyridine (Step D) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: [CH3:1][C:2]1([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=3)[CH:8]=2)[C:3]1=[O:21].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[C:3](=[O:21])[C:2]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([CH3:1])[CH2:11][CH2:10]3)=[N:13][CH:14]=1
Reactant: CCOC(=O)CC1(C)CCc2cc(-c3ccc([N+](=O)[O-])cn3)ccc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1(C)CCc2cc(-c3ccc(N)cn3)ccc2C1=O
Yield: 83.4 %

Procedure:
Iron powder (0.2 g, 3.58 mmol) was added to a solution of 3F (1.32 g, 3.58 mmol) in 10 mL of ethanol-water mixture (2:1) followed by NH4Cl (0.192 g, 3.58 mmol), and the mixture was refluxed for 3 h. The solvent was removed under reduced pressure, and residue was partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 25% ethyl acetate in hexane to afford the title compound (1.01 g, 82%) as a solid. 1H NMR (300 MHz, DMSO-d6): δ 8.05 (d, J=2.7 Hz, 1H), 7.94-7.86 (m, 3H), 7.74 (d, J=8.5 Hz, 1H), 7.00 (dd, J1=2.8 Hz, J2=8.6 Hz, 1H), 5.67 (s, 2H), 4.00 (q, J=7.2 Hz, 2H), 3.18-2.88 (m, 2H), 2.82 (d, J=15.8 Hz, 1H), 2.48-2.26 (m, 2H), 1.90 (dt, J1=13.2 Hz, J2=4.5 Hz, 1H), 1.17 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). ESI-MS m/z: 339 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[CH2:11]([N:13]([CH2:22][CH3:23])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1)[CH3:12]>CC(C)=O.C(O)C>[BrH:1].[BrH:1].[CH2:22]([N:13]([CH2:11][CH3:12])[C:14]([CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:7]2[CH:8]=[C:3]([CH3:2])[CH:4]=[CH:5][C:6]=2[CH3:9])[CH2:16]1)=[O:21])[CH3:23]
Reactant: CCN(CC)C(=O)c1cccnc1
Reactant: BrCc1ccc(CBr)cc1
Solvent: CCO
Solvent: CC(C)=O
Product: Br
Product: CCN(CC)C(=O)C1CCCN(c2cc(C)ccc2C)C1

Procedure:
Racemic (I) was synthesized as described by Quintana, et al. [J. Pharm. Sci. Vol. 54, Pages 785-787 (1965)] which is specifically incorporated herein by reference. Briefly, α,α'-dibromo-p-xylene (30.0 g, 0.11 36 mole) in 400 ml acetone was added to a solution of N,N-diethylnicotinamide (41.93 g, 0.2353 mole) in 700 ml absolute ethanol and refluxed (8.5 h) to yield α,α'-bis[3-(N,N-diethylcarbamoyl)pyridinium]-p-xylene dihydrobromide (36.3 g, 0.0585 mole, mp 267.4°-268.1° C.). Hydrogenation (PtO2,/H2, 50 psi) of the quaternary compound (25.0 g, 0.0403 mole) afforded I.2HBr (25.0 g, 0.0395 mole). The crude product (25.0 g) was dissolved in hot absolute ethanol and allowed to cool to room temperature. After three days, the separated crystals were filtered off to yield 9.4 g (0.0149 mole) of the "first crop", mp 280°-281° C. (decomp). The mother liquor, upon standing for 7-10 days afforded 6.5 g (0.0103 mole) of the "second crop", mp 279.0°-279.8° C. (decomp).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Br)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C(=O)([O-])O.[Na+].CN(C=O)C.[NH2:26][C:27]1[C:28]([CH3:42])=[C:29]([CH3:41])[C:30]2[O:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[C:31]=2[C:38]=1[CH:39]=[CH2:40]>C(OCC)(=O)C.O>[CH:39]([C:38]1[C:31]2[C:32](=[O:37])[C:33]([CH3:35])([CH3:36])[O:34][C:30]=2[C:29]([CH3:41])=[C:28]([CH3:42])[C:27]=1[N:26]1[CH2:14][CH2:13][N:4]([C:5]2[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1)=[CH2:40]
Reactant: COc1ccc(N(CCBr)CCBr)cc1
Reactant: C=Cc1c(N)c(C)c(C)c2c1C(=O)C(C)(C)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1c2c(c(C)c(C)c1N1CCN(c3ccc(OC)cc3)CC1)OC(C)(C)C2=O
Temperature: 120 °C
Reaction time: 16 h
Yield: 8.4 %

Procedure:
N,N-bis(2-bromoethyl)-4-methoxyaniline (2.45 g, 7.63 mmol) and sodium hydrogencarbonate (1.25 g, 1.40 mmol) were added to a solution of DMF (36 mL) containing 5-amino-4-ethenyl-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (1.47 g, 6.36 mmol) synthesized in Reference Example 22, and the mixture was stirred at 120° C. for 16 hours. After cooled to room temperature, water was added to the mixture, and extraction was performed using ethyl acetate. It was dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate: 100:0 to 90:10) to give 217 mg of the title compound (yield: 8%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.Br[C:10]1[CH:28]=[CH:27][C:13]([CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])=[CH:12][CH:11]=1.Br[C:30]1[CH:31]=C2C(=C[CH:38]=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=O)C2>>[CH2:38]([N:1]1[CH:5]=[C:4]([C:10]2[CH:28]=[CH:27][C:13]([CH2:14][NH:15][C:16]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[O:17])=[CH:12][CH:11]=2)[CH:3]=[N:2]1)[CH2:30][CH3:31]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: O=C(NCc1ccc(Br)cc1)N1Cc2ccccc2C1
Reactant: OB(O)c1cc[nH]n1
Product: CCCn1cc(-c2ccc(CNC(=O)N3Cc4ccccc4C3)cc2)cn1

Procedure:
The title compound was prepared as described in Example 280, substituting 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1H-pyrazol-3-ylboronic acid and N-(4-bromobenzyl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.5 Hz, 3H), 1.70-1.92 (m, 2H), 4.06 (t, J=6.9 Hz, 2H), 4.29 (d, J=6.1 Hz, 2H), 4.63 (s, 4H), 6.91 (t, J=5.9 Hz, 1H), 7.18-7.40 (m, 6H), 7.49 (d, J=8.5 Hz, 2H), 7.82 (s, 1H), 8.12 (s, 1H); MS (ESI(+)) m/e 361 (M+H)+.
Reaction SMILES: P(Cl)(Cl)[Cl:2].C(NC(C)C)(C)C.[CH:12]([N:15]([PH:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].C(O)C>C1(C)C=CC=CC=1>[CH:24]([N:20]([P:19]([N:15]([CH:12]([CH3:14])[CH3:13])[CH:16]([CH3:17])[CH3:18])[Cl:2])[CH:21]([CH3:23])[CH3:22])([CH3:26])[CH3:25]
Reactant: ClP(Cl)Cl
Reactant: CC(C)N(PN(C(C)C)C(C)C)C(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C

Procedure:
Bis(diisopropylamino)chlorophosphine was synthesized by reacting phosphorous trichloride and diisopropylamine in toluene. Fifty ml of the resulting bis(diisopropylamino)phosphine was placed in a 250 ml flask and 3.01 ml of ethanol added slowly over a two minute period and the reaction allowed to proceed for several days. After filtering the mixture and removing the solvent, the structure of the bis(diisopropylamino)ethylphosphite ester reagent was analyzed by 31P and 1H NMR (31P NMR in CD3CN 125.9 ppm).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:9]([CH3:22])[CH:8]=2)=[O:4].O1CCOCC1.O.[OH-].[Li+].Cl>O>[CH2:15]([O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[CH3:22])[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13]2)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)c(C)cc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2[nH]c(C(=O)O)cc2cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid methyl ester (1.3 g) in a mixed solvent of 1,4-dioxane (40 mL) and water (20 mL) was added Lithium hydroxide mono hydrate (1.8 g) at room temperature and this mixture was stirred at 50° C. for 1 hour. After this reaction mixture was cooled to room temperature, 1 mol/L hydrochloric acid was added. This precipitated solid was collected by filtration, and washed with water, dried under reduced pressure to give the title compound (1.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([N:43]1[C:48](=[O:49])[C:47](COS(C)(=O)=O)=[CH:46][C:45]([C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([CH3:63])[CH:57]=2)=[N:44]1)[CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1(C(OC(C)(C)C)=O)CCNC[CH2:65]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:47]2[C:48](=[O:49])[N:43]([CH2:34][CH:35]=[CH:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:44]=[C:45]([C:56]3[CH:61]=[CH:60][C:59]([F:62])=[C:58]([CH3:63])[CH:57]=3)[C:46]=2[CH3:65])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Product: Cc1cc(-c2nn(CC=Cc3ccccc3)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)ccc1F
Yield: 86.7 %

Procedure:
Following the procedure of Example 1 (10), 2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 86.7%).